Abstract
Microglia are the resident mononuclear immune cells of the central nervous system (CNS) and the activation of microglia contributes to the production of excessive neurotoxic factors. In particular, the overproduction of neurotoxic factors has critical effects on the development of brain injuries and neurodegenerative diseases. The human bone marrow-derived mesenchymal stem cells (hBM-MSCs) have blossomed into an effective approach with great potential for the treatment of neurodegenerative diseases and gliomas. The present study aimed to investigate the mechanism behind the therapeutic effect of hBM-MSCs on the activation of microglia in vitro. Specifically, the hBM-MSCs significantly inhibited the proliferation of lipopolysaccharide-activated microglial cells (LPS)-activated microglial cells. Additionally, we investigated whether the adenosine-monophosphate-activated protein kinase signaling (AMPK) pathway was involved in this process. Our data demonstrated that hBM-MSCs significantly increased the phosphorylated AMPK in LPS-activated microglial cells. In addition, our study indicated the inhibitory effect of hBM-MSCs on the pro-inflammatory mediators and oxidative stress by the AMPK pathway in LPS-activated microglial cells. These results could shed light on the understanding of the molecular basis for the inhibition of hBM-MSCs on LPS-activated microglial cells and provide a molecular mechanism for the hBM-MSCs implication in brain injuries and neurodegenerative diseases.
This is a preview of subscription content, log in via an institution to check access.
References
Baron R, Binder A, Wasner G (2010) Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol 9(8):807–819. https://doi.org/10.1016/S1474-4422(10)70143-5
Blaylock RL (2017) Parkinson’s disease: microglial/macrophage-induced immunoexcitotoxicity as a central mechanism of neurodegeneration. Surg Neurol Int 8:65. https://doi.org/10.4103/sni.sni_441_16
Bollinger JL, Bergeon Burns CM, Wellman CL (2016) Differential effects of stress on microglial cell activation in male and female medial prefrontal cortex. Brain Behav Immun 52:88–97. https://doi.org/10.1016/j.bbi.2015.10.003
Borst K, Schwabenland M, Prinz M (2018) Microglia metabolism in health and disease. Neurochem Int. https://doi.org/10.1016/j.neuint.2018.11.006
Cabezas R, Baez-Jurado E, Hidalgo-Lanussa O, Echeverria V, Ashraf GM, Sahebkar A, Barreto GE (2018) Correction to: growth factors and neuroglobin in astrocyte protection against neurodegeneration and oxidative stress. Mol Neurobiol. https://doi.org/10.1007/s12035-018-1257-8
Carniglia L, Ramirez D, Durand D, Saba J, Turati J, Caruso C, Scimonelli TN, Lasaga M (2017) Neuropeptides and microglial activation in inflammation, pain, and neurodegenerative diseases. Mediat Inflamm 2017:5048616. https://doi.org/10.1155/2017/5048616
Chakari-Khiavi F, Dolati S, Chakari-Khiavi A, Abbaszadeh H, Aghebati-Maleki L, Pourlak T, Mehdizadeh A, Yousefi M (2019) Prospects for the application of mesenchymal stem cells in Alzheimer’s disease treatment. Life Sci 231:116564. https://doi.org/10.1016/j.lfs.2019.116564
Crosas-Molist E, Fabregat I (2015) Role of NADPH oxidases in the redox biology of liver fibrosis. Redox Biol 6:106–111. https://doi.org/10.1016/j.redox.2015.07.005
Dheen ST, Kaur C, Ling EA (2007) Microglial activation and its implications in the brain diseases. Curr Med Chem 14(11):1189–1197
Drela K, Siedlecka P, Sarnowska A, Domanska-Janik K (2013) Human mesenchymal stem cells in the treatment of neurological diseases. Acta Neurobiol Exp 73(1):38–56
Franco R, Fernandez-Suarez D (2015) Alternatively activated microglia and macrophages in the central nervous system. Prog Neurobiol 131:65–86. https://doi.org/10.1016/j.pneurobio.2015.05.003
Graeber MB, Li W, Rodriguez ML (2011) Role of microglia in CNS inflammation. FEBS Lett 585(23):3798–3805. https://doi.org/10.1016/j.febslet.2011.08.033
Haslund-Vinding J, McBean G, Jaquet V, Vilhardt F (2017) NADPH oxidases in oxidant production by microglia: activating receptors, pharmacology and association with disease. Br J Pharmacol 174(12):1733–1749. https://doi.org/10.1111/bph.13425
Her GJ, Wu HC, Chen MH, Chen MY, Chang SC, Wang TW (2013) Control of three-dimensional substrate stiffness to manipulate mesenchymal stem cell fate toward neuronal or glial lineages. Acta Biomater 9(2):5170–5180. https://doi.org/10.1016/j.actbio.2012.10.012
Hou L, Wang K, Zhang C, Sun F, Che Y, Zhao X, Zhang D, Li H, Wang Q (2018) Complement receptor 3 mediates NADPH oxidase activation and dopaminergic neurodegeneration through a Src-Erk-dependent pathway. Redox Biol 14:250–260. https://doi.org/10.1016/j.redox.2017.09.017
Jose S, Tan SW, Ooi YY, Ramasamy R, Vidyadaran S (2014) Mesenchymal stem cells exert anti-proliferative effect on lipopolysaccharide-stimulated BV2 microglia by reducing tumour necrosis factor-alpha levels. J Neuroinflamm 11:149. https://doi.org/10.1186/s12974-014-0149-8
Karussis D, Kassis I, Kurkalli BG, Slavin S (2008) Immunomodulation and neuroprotection with mesenchymal bone marrow stem cells (MSCs): a proposed treatment for multiple sclerosis and other neuroimmunological/neurodegenerative diseases. J Neurol Sci 265(1–2):131–135. https://doi.org/10.1016/j.jns.2007.05.005
Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91(2):461–553. https://doi.org/10.1152/physrev.00011.2010
Kumar A, Henry R, Stoica B, Loane D, Abulwerdi G, Bhat S, Faden A (2018) Neutral sphingomyelinase inhibition alleviates LPS induced microglia activation and neuroinflammation after experimental traumatic brain injury. J Pharmacol Exp Ther. https://doi.org/10.1124/jpet.118.253955
Lee DY, Oh YJ, Jin BK (2005) Thrombin-activated microglia contribute to death of dopaminergic neurons in rat mesencephalic cultures: dual roles of mitogen-activated protein kinase signaling pathways. Glia 51(2):98–110. https://doi.org/10.1002/glia.20190
Lewerenz J, Ates G, Methner A, Conrad M, Maher P (2018) Oxytosis/ferroptosis-(Re-) emerging roles for oxidative stress-dependent non-apoptotic cell death in diseases of the central nervous system. Front Neurosci 12:214. https://doi.org/10.3389/fnins.2018.00214
Lim SY, Subedi L, Shin D, Kim CS, Lee KR, Kim SY (2017) A new neolignan derivative, balanophonin isolated from firmiana simplex delays the progress of neuronal cell death by inhibiting microglial activation. Biomol Ther 25(5):519–527. https://doi.org/10.4062/biomolther.2016.224
Mukherjee P, Mulrooney TJ, Marsh J, Blair D, Chiles TC, Seyfried TN (2008) Differential effects of energy stress on AMPK phosphorylation and apoptosis in experimental brain tumor and normal brain. Mol Cancer 7:37. https://doi.org/10.1186/1476-4598-7-37
Oh KW, Moon C, Kim HY, Oh SI, Park J, Lee JH, Chang IY, Kim KS, Kim SH (2015) Phase I trial of repeated intrathecal autologous bone marrow-derived mesenchymal stromal cells in amyotrophic lateral sclerosis. Stem Cells Transl Med 4(6):590–597. https://doi.org/10.5966/sctm.2014-0212
Popiolek-Barczyk K, Mika J (2016) Targeting the microglial signaling pathways: new insights in the modulation of neuropathic pain. Curr Med Chem 23(26):2908–2928
Qiao H, Zhou Y, Qin X, Cheng J, He Y, Jiang Y (2018) NADPH oxidase signaling pathway mediates mesenchymal stem cell-induced inhibition of hepatic stellate cell activation. Stem Cells Int 2018:1239143. https://doi.org/10.1155/2018/1239143
Song WM, Colonna M (2018) The microglial response to neurodegenerative disease. Adv Immunol 139:1–50. https://doi.org/10.1016/bs.ai.2018.04.002
Steens J, Klein D (2018) Current strategies to generate human mesenchymal stem cells in vitro. Stem Cells Int 2018:6726185. https://doi.org/10.1155/2018/6726185
Subedi L, Ji E, Shin D, Jin J, Yeo JH, Kim SY (2017) Equol, a dietary daidzein gut metabolite attenuates microglial activation and potentiates neuroprotection in vitro. Nutrients. https://doi.org/10.3390/nu9030207
Togna AR, Latina V, Trefiletti G, Guiso M, Moschini S, Togna GI (2013) 1-Phenil-6,7-dihydroxy-isochroman inhibits inflammatory activation of microglia. Brain Res Bull 95:33–39. https://doi.org/10.1016/j.brainresbull.2013.03.001
Trallori E, Ghelardini C, Di Cesare Mannelli L (2019) Mesenchymal stem cells, implications for pain therapy. Neural Regen Res 14(11):1915–1916. https://doi.org/10.4103/1673-5374.259615
Wilhelmsson U, Andersson D, de Pablo Y, Pekny R, Stahlberg A, Mulder J, Mitsios N, Hortobagyi T, Pekny M, Pekna M (2017) Injury leads to the appearance of cells with characteristics of both microglia and astrocytes in mouse and human brain. Cereb Cortex 27(6):3360–3377. https://doi.org/10.1093/cercor/bhx069
Xue Y, Wang Y, Feng DC, Xiao BG, Xu LY (2008) Tetrandrine suppresses lipopolysaccharide-induced microglial activation by inhibiting NF-kappaB pathway. Acta Pharmacol Sin 29(2):245–251. https://doi.org/10.1111/j.1745-7254.2008.00734.x
Yan ZJ, Hu YQ, Zhang HT, Zhang P, Xiao ZY, Sun XL, Cai YQ, Hu CC, Xu RX (2013) Comparison of the neural differentiation potential of human mesenchymal stem cells from amniotic fluid and adult bone marrow. Cell Mol Neurobiol 33(4):465–475. https://doi.org/10.1007/s10571-013-9922-y
Zhai X, Qiao H, Guan W, Li Z, Cheng Y, Jia X, Zhou Y (2015) Curcumin regulates peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression by AMPK pathway in hepatic stellate cells in vitro. Eur J Pharmacol 746:56–62. https://doi.org/10.1016/j.ejphar.2014.10.055
Zhan L, Krabbe G, Du F, Jones I, Reichert MC, Telpoukhovskaia M, Kodama L, Wang C, Cho SH, Sayed F, Li Y, Le D, Zhou Y, Shen Y, West B, Gan L (2019) Proximal recolonization by self-renewing microglia re-establishes microglial homeostasis in the adult mouse brain. PLoS Biol 17(2):e3000134. https://doi.org/10.1371/journal.pbio.3000134
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Cao, D., Qiao, H., He, D. et al. Mesenchymal stem cells inhibited the inflammation and oxidative stress in LPS-activated microglial cells through AMPK pathway. J Neural Transm 126, 1589–1597 (2019). https://doi.org/10.1007/s00702-019-02102-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-019-02102-z